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An NCI-designated Comprehensive Cancer Center, affiliated with the University of Pittsburgh School of Medicine
Research
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My laboratory is focused on developing novel clinical models of glioma and identifying druggable targets to facilitate early phase clinical trials.
Gliomas are intensely heterogenous tumors that not only contain numerous cell types, but also demonstrate the ability to transition between different phenotypic states. This complexity has made developing model systems that recapitulate human tumor biology both difficult and essential. Traditionally, models of gliomas are 2-dimensional cell lines and only represent certain subtypes of the highest-grade glioma, glioblastoma. This is because the unique biology of lower grade gliomas has prevented them from being studied either outside of the lab or in animals. We have created ex-vivo culture systems that allow us to investigate critical aspects of the tumor microenvironment, immune response, and discover targets for therapy. Our laboratory has previously shown the ability to establish lower grade glioma organoids in vitro, maintain those cultures for extended periods of time, hibernate, and then reanimate tumor tissue without loss of either genetic or phenotypic fidelity. Our work also includes extensive and sophisticated live-cell imaging analysis that allows for longitudinal, non-invasive assessment of organoid response to treatment.
Our organoid model systems, in addition to glioma stem cell and mouse models, allow us to perform highly sophisticated assessments of drug response across platforms, and identify rare but critical druggable targets in gliomas. These analyses include complex metabolic tracing and immune cell response assessment. Despite the fundamental principles of genomics, immunology, and cellular cancer biology that underlie our work, our group focuses on projects that have high potential for immediate clinical translation.
The lab has a focus on several topics:
1) It is now appreciated that HGG glioma comprises of several molecular subgroups and that the genetics of pediatric and adult HGG are distinct. Therefore a “one size that fits all” approach to therapy will not be successful. The Agnihotri Laboratory interests include using next-generation sequencing technology to identify and validate driver alterations of various HGG with a focus on DIPG and non-histone mutated “RTK” Glioblastoma (GBM).
2) A defining hallmark of glioblastoma and DIPG is altered tumor metabolism. The metabolic shift towards aerobic glycolysis with reprogramming of mitochondrial oxidative phosphorylation, regardless of oxygen availability, is a phenomenon known as the Warburg effect. In addition to the Warburg effect, glioblastoma tumor cells also utilize the tricarboxylic acid cycle/oxidative phosphorylation in a different capacity than normal tissue. The Agnihotri Laboratory investigates the metabolic dependencies of brain tumors and if they can provide therapeutic vulnerabilities.
3) The lab uses the genomic and metabolic information to build better representative brain tumor pre-clinical models for testing of novel therapies. Working closely with a clinical team use of these accurate models are essential to start early phase clinical trials.
The central theme of my research program is to investigate the metabolic and epigenetic control of senescence in the context of cancer. Cellular senescence is a stable cell cycle arrest that can be both tumor suppressive and tumor promoting in a highly context-dependent manner. Relatively little is known about metabolic changes that either induce or inhibit senescence. Using a combination of cell and molecular biology tools in addition to high-throughput approaches such as metabolomics and functional (epi)-genomics, my laboratory aims to mechanistically understand how to induce or overcome senescence. Our studies also include aspects of translational research utilizing both ovarian cancer and melanoma models to explore whether these newly-identified metabolic and epigenetic pathways can be targeted for novel cancer therapies. The lab is currently funded by: 1) an NCI R37 MERIT Award to understand pro-tumorigenic nucleotide metabolism in melanomagenesis; 2) an American Cancer Society Research Scholar Grant to investigate the role of isocitrate dehydrogenase 1 (IDH1)-mediated alpha-ketoglutarate production in histone methylation at homologous recombination genes in ovarian cancer; and 3) 2 NRSA F31s elucidating various metabolic and epigenetic mechanisms in ovarian cancer senescence. Pending grants include the role of nuclear acetyl-CoA production on histone acetylation and DNA damage response in ovarian cancer (NCI mPI R01) and how macropinocytosis of branched chain amino acids affects both tumor cell-intrinsic and immune cell responses to therapy (DoD Ovarian Cancer Research Program, a collaboration with Dr. Greg Delgoffe).
Oleg E. Akilov, MD, PhD, is an Assistant Professor of the Department of Dermatology at the University of Pittsburgh and a Director of the Cutaneous Lymphoma Program and Extracorporeal Photopheresis Unit. Dr. Akilov directs Cutaneous Lymphoma Program providing the full spectrum of management of all stages of cutaneous lymphoma. He serves as a principal investigator on multiple clinical trials in cutaneous lymphoma. Additionally, Dr. Akilov is very enthusiastic about resident education and mentoring future dermatologists.
Dr. Altschuler's laboratory studies mechanisms of signal transduction by the second messenger cAMP in cell proliferation. cAMP-dependent protein kinase (PKA) and Exchange protein activated by cAMP (Epac) represent the main effectors of cAMP action. Both pathways converge at the level of the small GTPase Rap1b, via its Epac-mediated activation and PKA-mediated phosphorylation. The role of Rap1 activation (Epac) and phosphorylation (PKA) coordinating the early rate-limiting events in cAMP-dependent cell proliferation are studied using a multidisciplinary approach including molecular and cellular biology techniques in vitro, as well as in vivo validation using transgenic/knock in technologies in endocrine tumor models.
Millions of people are infected with both HIV and HBV. Morbidity and mortality in HIV/HBV co-infection is higher than mono-infections and co-infection accelerates HBV-related liver disease with more frequent development of hepatocellular carcinoma (HCC), particularly when CD4 cell counts are low. Together with Dr. Haitao Guo, we will develop a murine model to study pathogenesis and HCC progression during HIV/HBV co-infection, which will be essential in evaluating mechanisms of infection as well as novel prevention methods, improved therapies, and curative strategies.
A critical question to ask, particularly in this genomic era, is how organisms interpret the vast amounts of information encoded in their genomes. The Arndt lab studies the first step in gene expression, the synthesis of mRNA by RNA polymerase II, with a focus on the mechanisms that regulate transcription in the chromatin environment of a eukaryotic cell. The fundamental importance of understanding transcriptional regulation is evident from the large number of human developmental defects and diseases, including cancer and AIDS, that arise when cellular transcription factors are altered by mutation or commandeered by viral proteins.
